Local c-di-GMP signaling, triggered by cross-regulation of cAMP-CRP and c-di-GMP, controls biofilm formation under nutrient limitation

作者：Di Sun, Xiaobo Liu, Ying Zhang, Rui Shi, Yi Ru, Xuge Zhou, Ying Chen, Jing Yang, Jiawen Liu, Jingrong Zhu, Cong Liu, Weijie Liu · 发表于：Proceedings of the National Academy of Sciences · 年份：2025 · DOI：10.1073/pnas.2516964122 · 被引用次数：10 · 研究领域：Bacterial biofilms and quorum sensing、Bacterial Genetics and Biotechnology、Oral microbiology and periodontitis research

Bacteria have several nucleotide second messengers, most of which act as global regulators to control a wide range of bacterial physiological processes. Studies usually focus on a single second messenger, and the mechanisms and physiological significance of the cross-regulation between different nucleotide second messengers are often unclear. Here, we show that Shewanella putrefaciens can form biofilms in both nutrient-rich and nutrient-poor media. While both are controlled by c-di-GMP, the regulatory models differ. Under low nutrient conditions, cross-regulation of cAMP-CRP and c-di-GMP occurs at the transcriptional and posttranslational levels, thereby controlling biofilm development. During the early stages of biofilm development, cAMP-CRP directly promotes the transcription of a PDE gene, lrbR , by LrbA. Additionally, cAMP-CRP recruits LrbR to BpfD to suppress early biofilm formation via LrbR-dependent local degradation of c-di-GMP. Finally, as intracellular LrbR levels decrease, cAMP-CRP-BpfD enables a rapid shift to biofilm development and supports biofilm maintenance. Under high nutrient conditions, this cross-regulation does not occur, resulting in a positive correlation between global c-di-GMP levels and biofilm biomass. The identification of distinct modes of biofilm regulation in different nutrients will provide a theoretical basis for future targeted control of biofilm formation in different nutrient environments.